A major obstacle to AIDS vaccine and therapeutic development is the incomplete understanding of what constitutes protective immunity to HIV- 1. To study the role of humoral immunity in preventing HIV infection, we are investigating antibody neutralization of primary and laboratory HIV-1 isolates. Using a variety of novel culture methods we are anlyzing both polyclonal and monoclonal antibodies sensitivity patterns of a variety of HIV-1 types. We are finding that the ability to neutralize HIV depends not only on the antibody repertoire of an individual but also on the virus phenotype growing in the patient. We have discovered that the predominant form of HIV transmitted in the population (primary HIV-1) escapes from immunity because its neutralizing sites are cryptic or hidden on the membrane form of the virus. Our findings have important implications for HIV transmission and vaccine development efforts. Novel assays with monoclonal antibodies and type specific antisera should provide methods to immunotype patient isolates and to evaluate humoral responses to HIV vaccine candidates in clinical trials. Studies are planned on heterosexual virus transmission and on developing assays to measure antiviral compounds used in vaginal products.